{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T19:47:20Z","timestamp":1783021640162,"version":"3.54.6"},"reference-count":45,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2022,2,16]],"date-time":"2022-02-16T00:00:00Z","timestamp":1644969600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK099275"],"award-info":[{"award-number":["DK099275"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK107585"],"award-info":[{"award-number":["DK107585"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Infections with non\u2010typhoidal <jats:italic>Salmonella<\/jats:italic> spp. represent the most burdensome foodborne illnesses worldwide, yet despite their prevalence, the mechanism through which <jats:italic>Salmonella<\/jats:italic> elicits diarrhoea is not entirely known. Intestinal ion transporters play important roles in fluid and electrolyte homeostasis in the intestine. We have previously shown that infection with <jats:italic>Salmonella<\/jats:italic> caused decreased colonic expression of the chloride\/bicarbonate exchanger SLC26A3 (down\u2010regulated in adenoma; DRA) in a mouse model. In this study, we focused on the mechanism of DRA downregulation during <jats:italic>Salmonella<\/jats:italic> infection, by using murine epithelial enteroid\u2010derived monolayers (EDMs). The decrease in DRA expression caused by infection was recapitulated in EDMs and accompanied by increased expression of Atonal Homolog 1 (ATOH1), the goblet cell marker Muc2 and the enteroendocrine cell marker ChgA. This suggested biased epithelial differentiation towards the secretory, rather than absorptive phenotype. In addition, the downstream Notch effector, Notch intracellular domain (NICD) and Hes1 were decreased following <jats:italic>Salmonella<\/jats:italic> infection. The relevance of Notch signalling was further investigated using a \u03b3\u2010secretase inhibitor, which recapitulated the downregulation in Hes1 and DRA as well as upregulation in ATOH1 and Muc2 seen following infection. Our findings suggest that <jats:italic>Salmonella<\/jats:italic> infection may result in a shift from absorptive to secretory cell types through Notch inhibition, which explains why there is a decreased capacity for absorption and ultimately the accumulation of diarrhoeal fluid. Our work also shows the value of EDMs as a model to investigate mechanisms that might be targeted for therapy of diarrhoea caused by <jats:italic>Salmonella<\/jats:italic> infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p><jats:italic>Salmonella<\/jats:italic> is a leading foodborne pathogen known to cause high\u2010chloride\u2010content diarrhoea.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>Salmonella<\/jats:italic> infection of murine enteroid\u2010derived monolayers decreased DRA expression.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>Salmonella<\/jats:italic> infection resulted in upregulation of the secretory epithelial marker ATOH1, the goblet cell marker Muc2 and the enteroendocrine cell marker ChgA.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Downregulation of DRA may result from infection\u2010induced Notch inhibition, as reflected by decreased expression of Notch intracellular domain and Hes1, as well as from decreased HNF1\u03b1 signalling.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The imbalance in intestinal epithelial differentiation favouring secretory over absorptive cell types is a possible mechanism by which <jats:italic>Salmonella<\/jats:italic> elicits diarrhoea and may be relevant therapeutically.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp282585","type":"journal-article","created":{"date-parts":[[2022,2,1]],"date-time":"2022-02-01T00:13:30Z","timestamp":1643674410000},"page":"1851-1865","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Diarrhoeal pathogenesis in <i>Salmonella<\/i> infection may result from an imbalance in intestinal epithelial differentiation through reduced Notch signalling"],"prefix":"10.1113","volume":"600","author":[{"given":"Andrew","family":"Quach","sequence":"first","affiliation":[{"name":"School of Medicine, Division of Gastroenterology Department of Medicine University of California San Diego  La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashini R.","family":"Jayaratne","sequence":"additional","affiliation":[{"name":"School of Medicine, Division of Gastroenterology Department of Medicine University of California San Diego  La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beom Jae","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Medicine, Division of Gastroenterology Department of Medicine University of California San Diego  La Jolla CA USA"},{"name":"Department of Gastroenterology Korea University Guro Hospital  Seoul Republic of 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